Paramyxoviruses have been implicated in both animal and human infections. Paramyxoviruses include mumps virus, measles virus, respiratory syncytial virus (RSV) and parainfluenza virus. RSV is the major cause of bronchiolitis and pneumonia in infants and children. Parainfluenza viruses are the second most common causes of respiratory tract disease in infants and children, and can cause pneumonia, bronchitis and croup in children and the elderly.
In 1994, a fatal infection in horses and humans in Australia was identified to be caused by a new paramyxovirus, Hendra virus (HeV). In 1998, a closely related virus, Nipah virus (NiV), was responsible for fatal infections in pigs and humans in Malaysia. Wild T. F. Henipaviruses: a new family of emerging Paramyxoviruses. Pathol Biol (Paris). 57(2):188-96 (2009). HeV and NiV, which are in the Henipavirus genus of the Paramyxoviridae family, are contagious and highly virulent. They are capable of infecting a number of mammalian species and causing potentially fatal disease. For example, NiV and HeV cause encephalitis in humans, with fatality rates of up to 75%. O'Sullivan et al. Fatal encephalitis due to novel paramyxovirus transmitted from horses. Lancet 349, 93-95 (1997). Chua et al. Nipah virus: a recently emergent deadly paramyxovirus. Science 288, 1432-1435 (2000). Wang et al. Molecular biology of Hendra and Nipah viruses. Microbes and infection/Institut Pasteur 3, 279-287 (2001). As the viruses evolve, they can now be directly transmitted from its fruit bat mammalian reservoir to humans, bypassing the pig host which served as an intermediate. Human-to-human transmission has also become a primary mode of NiV spread. Enserink, M. Emerging infectious diseases. Nipah virus (or a cousin) strikes again. Science 303, 1121 (2004). Butler, D. Fatal fruit bat virus sparks epidemics in southern Asia. Nature 429, 7 (2004). In addition to acute infection, both NiV and HeV can cause asymptomatic infection in up to 60% of exposed population, which may lead to late-onset disease or relapse of encephalitis years after initial infection, as well as persistent or delayed neurological sequelae. Sejvar et al. Long-term neurological and functional outcome in Nipah virus infection. Annals of Neurology 62, 235-242 (2007).
Paramyxoviruses have viral envelopes covering their protein capsids. The nucleocapsid core is composed of the genomic RNA, nucleocapsid proteins, phosphoproteins and polymerase proteins. The viral envelopes typically are derived from portions of the host cellular membranes (phospholipids and proteins), further containing some viral glycoproteins. Glycoproteins on the surface of the viral envelope can bind to receptors on the host cellular membrane. To initiate infection, the lipid bilayer of an enveloped virus fuses with a cellular membrane for delivery of the viral nucleocapsid to the host cell cytoplasm.
Specifically, the first step in the infection of a cell by HeV or NiV is the binding of the virus to the target cells, via interaction of the viral receptor-binding protein G (HeV G) with the specific cellular receptors, namely, receptor Ephrin B2 (EFNB2) for HeV, EFNB2 and EFNB3 for NiV. Then the viral fusion protein F (HeV F) mediates the fusion of the viral envelope with the plasma membrane of the cell. Upon binding to the cellular receptor, HeV G triggers HeV F to convert from its native state to fusion-activated form with the fusion domain exposed. The correct timing of HeV F activation is critical for viral entry: activation must occur only when HeV F is in contact with the target cell membrane. Porotto et al. Influence of the human parainfluenza virus 3 attachment protein's neuraminidase activity on its capacity to activate the fusion protein. Journal of virology 79, 2383-2392 (2005). Porotto et al. Triggering of human parainfluenza virus 3 fusion protein (F) by the hemagglutinin-neuraminidase (FIN): an I-IN mutation diminishing the rate of F activation and fusion. J. Virol. 77, 3647-3654 (2003). Russell et al. Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion. EMBO 20, 4024-4034 (2001).
Although HeV and NiV were discovered in the 1990's, there still has been a lack of licensed vaccines or antiviral therapies against HeV or NiV. Accordingly, HeV and NiV are designated as biosafety level (BSL) 4 agents. Development of a therapy against henipavirues is in urgent need.
We have developed an approach to reduce the viral infectivity of henipavirus, where particles coated with a lipid bilayer and cellular receptors are used to inactivate henipaviruses specifically. This antiviral method can be used to treat, diminish or prevent viral infections caused by henipaviruses and other paramyxoviruses, as well as enveloped viruses in general.